Poly(ADP-ribose) polymerase inhibitor increases growth inhibition and reduces G(2)/M cell accumulation induced by temozolomide in malignant glioma cells.

Abstract

Temozolomide (TZM) is a novel methylating agent currently under investigation for treatment of recurrent high-grade gliomas. Although TZM generates a wide spectrum of methyl adducts, its cytotoxicity has been attributed to mismatch repair (MR)-mediated processing of O(6)-methylguanine:T mispairs. N3-methyladenine and N7-methylguanine adducts are promptly repaired by the base excision repair system, unless a poly(ADP-ribose) polymerase (PARP) inhibitor is combined to TZM. In this case, the repair process of N-methylpurines cannot be completed and the deriving DNA strand breaks contribute to cytotoxicity. In this study, we investigated the influence on cell growth and cell cycle of treatment with TZM + PARP inhibitor in glioma cells characterized by different susceptibility to TZM. The results indicated that PARP inhibitor increases growth inhibition induced by TZM in either p53-wild-type or p53-mutant glioblastoma cells, as early as 24 h after drug exposure. The enhancing effect exerted by PARP inhibitor was particularly evident in glioma cells characterized by a defective expression of MR, since these cells are tolerant to O(6)-methylguanine damage and show low sensitivity to TZM. In O(6)-alkylguanine-DNA alkyltransferase (OGAT)-deficient and MR-proficient tumor cells bearing wild-type p53, the drug combination markedly reduced cell accumulation in the G(2)/M phase of cell cycle and induction of the G(2) checkpoint regulator Chk1 kinase. In short-term cultures of glioma cells derived from surgical specimens, PARP inhibitor enhanced chemosensitivity to TZM and this effect was especially evident in OGAT-proficient tumors. Thus, a pharmacological strategy based on the interruption of N-methylpurine repair might represent a novel strategy to restore or increase glioma sensitivity to TZM.

• Authors: Lucio Tentori, Ilaria Portarena, Francesco Torino, Massimo Scerrati, Pierluigi Navarra, Grazia Graziani
• Journal: Glia (Glia) Vol. 40 Issue 1 Pg. 44-54 (Oct 2002) ISSN: 0894-1491 [Print] United States
• PMID: 12237842 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2002 Wiley-Liss, Inc.

Chemical References

• Antineoplastic Agents, Alkylating
• Benzamides
• Cell Cycle Proteins
• Enzyme Inhibitors
• Proteins
• Tumor Suppressor Protein p53
• Dacarbazine
• 3-aminobenzamide
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases
• Protein Kinases
• CHEK1 protein, human
• Checkpoint Kinase 1
• CDC25C protein, human
• cdc25 Phosphatases
• Temozolomide

Topics

• Antineoplastic Agents, Alkylating (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Benzamides (pharmacology)
• Brain Neoplasms (drug therapy, enzymology, genetics)
• Cell Cycle Proteins (drug effects, genetics, metabolism)
• Checkpoint Kinase 1
• DNA Repair (drug effects, genetics)
• Dacarbazine (analogs & derivatives, pharmacology)
• Down-Regulation (drug effects, genetics)
• Drug Interactions
• Drug Resistance, Neoplasm (genetics)
• Drug Therapy, Combination
• Enzyme Inhibitors (pharmacology)
• G2 Phase (drug effects, genetics)
• Glioblastoma (drug therapy, enzymology, genetics)
• Glioma (drug therapy, enzymology, genetics)
• Humans
• Mitosis (drug effects, genetics)
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases
• Protein Kinases (drug effects, genetics, metabolism)
• Proteins (antagonists & inhibitors, metabolism)
• Temozolomide
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (drug effects, genetics, metabolism)
• Up-Regulation (drug effects, genetics)
• cdc25 Phosphatases (drug effects, genetics, metabolism)